Hexamethylene tetramine salts of aromatic acids



Patented Nov. 14, 1939 UNITED STATES HEXAMETHYLENE TETRAIVHNE SALTS 01EAROM ATIQ ACIDS Monroe D. Edehnan, New York, and Edmond T.

Tisza, Yonkers, N. Y, assignors to Pyridium Corporation, Nepal-a Park,New York, N. Y.,

a corporation of New York No Drawing. Application June 10, 1937,

Serial No. 147,510

10 Claims.

This invention relates to improvements in hexamethyl tetramine salts ofaromatic acids, particularly to non-toxic antiseptics for the treatmentof infections of the urinary tract.

5 A few years ago ketogenic diet was recommended for the treatment ofcertain urinary infections. It has been found that the bactericidalagent in the urine, resulting from the ketcgenic diet is betahydroxybutyric acid. It appears, there-fore, that by the administrationof this acid one would obtain similar results. However, when betahydroxybutyric acid or similar aliphatic acids are administered. orallythey are largely oxidized in the body into carbon dioxide 5' and waterbefore reaching the kidney, therefore they are not eliminated in theurinary tract. Some of the orally administered beta hydroxybutyric acidmay get to the urinary tract when the patient is on the ketogenic diet,that is, when the patients metabolism is not normal.

The case is different with the aromatic acids having the carboxyl groupon the side chain. These acids eliminate through the urinary tractunchanged and it has been shown that if the side chain does not containa hydroxy group the body will add such a group to it before it is passedout through the urine.

Such an aromatic acid with the hydroxy group on the side chain is, forinstance, mandelic acid. This acid is recommended for the treatment ofinfections of the urinary tract, but to accomplish satisfactory resultsit necessary to administer not less than 12 gms. daily. Besides this.large dose it is found to be necessary to administer simultaneously alarge amount of ammonium chloride or other acidifying agents to lowerthe pH of the urine. The gastric disturb-- ance caused by this treatmentmakes its use very undesirable.

It is known that the bactericidal action of aliphatic acids is increasedwith the number of the carbon atoms in it. We have found that similarconditions exist when the length of the side chain is increased inaromatic acids.

Another Well known urinary antiseptic is hexamethylenetetramine,hereafter called shortly, methenamine. Methenamine itself is a valuableurinary antiseptic because it liberates formaldehyde in the acid oracidified medium or" the urinary tract.

An object of this invention is to combine methenamine with aromaticacids in such a form that they will be eliminated unchanged through theurinary tract, where the acid, combined with the methenamine, willliberate formaldehyde and so exert combined antiseptic action.

Another object of. this invention is to prepare compounds which willproduce satisfactory therapeutic results, if administered in relativelysmall quantities.

A further object of this invention is to increase the bactericidalaction of side chain aromatic acids by combining them with methenamine.

Further objects will be seen from the specification.

We have found that aromatic acids combined with met'nenamine exertbactericidal action Whether the side chain is saturated or unsatu rated,and whether a hydroxyl group is attached to it or not.

Methane-mine itself shows very little bactericidal action when tested invitro, by the agar plate method. When a salt of methenamine is made withside chain organic acids, the bactericidal action increases considerablywhen tested by the same method. The increase of bactericidal actionseems to be depending, to a certain extent, on the length of the sidechain, and for practical purposes a chain consisting of not less thantwo and not more than six carbon atoms is preferred.

These salts of methenamine with side chain aromatic acids are preparedby dissolving equimolecular quantities of methenamine and the acid innon-aqueous solvents, such as absolute alcohols, acetone, chlorinatedhydrocarbons, etc., refluxing the solutions from five minutes toone-half an hour, depending on the quantities, cooling the solution andcollecting the crystals on a filter. They form white crystallineproducts which can be purified by recrystallizing from suitablesolvents. As methenamine is monobasic it combines with one molecule ofthe aromatic acid used.

Example 1 6.8 g. phenylacetic acid and 7.0 grams methenamine weredissolved in 40 cc. dry methanol, filtered and concentrated on the steambath until the solution. became saturated. After cooling the crystalswere collected on a filter, washed and recrystallized out of chloroform,and dried at room temperature. The White crystalline plates have nodefinite melting point. They soften to a viscous gummy substance atabout 80 to 90 C.

The formula of the new product is CsI-I12N4.CsH5CH2COOI-I methenaminephenylacetate.

Example 2 5 grams hydrocinnamic (phenylpropionic) acid and 4.67 gramsmethenamine were dissolved in 30 cc. hot chloroform and refluxed forfive minutes. The solution was filtered and concentrated on the steambath until beginning of crystallization. After cooling on ice thecrystals are collected, washed and recrystallized from chlorofrom. Themelting point of the crystalline plates is 124-125" C.

The formula of the new compound is C6H12N4.CsH5-CH2-CH2COOH methenamine,8 phenyl propionate.

Example 3 CsH12N4.CeH5-CH2CH2CH2COOH methenamine 'y phenylbutyrate.

Example 4 7.4 grams cinnamic (phenyl acrylic) acid and 7.1 gramsmethenamine are dissolved in 40 cc. chloroform and boiled for fiveminutes to obtain a complete reaction. The solution is filtered and thechloroform is evaporated until crystals begin to appear. After cooling,the crystals are collected, washed and recrystallized out of chloroformor benzene. The melting point of the crystalline plates is 133 to 134 C.

The formula of the new compound is:

CsH12N4.CsI-I5CH=CH-COOH methenamine cinnamate.

Example 5 4.2 grams (3 oxyhydrocinnamic (c oxy p phenyl propionic) acidand 3.5 grams methenamine were dissolved in 25 cc. hot chloroform. Thesolution was filtered and concentrated to a small volume on the steambath. After cooling on ice the crystals are collected, Washed andrecrystallized out of chloroform. The crystalline plates begin to softenat to C., and the melting point is 141 to 143 C.

The formula of the new compound is:

methenamine B oxy-fl-phenyl propionate.

The products described in the above examples are of similar character.They all form white crystalline plates, soluble in water, alcohol,chloroform, benzene, insoluble in ligroin.

The new compounds show a decided bactericidal action against cocci andbacilli, which is considerably higher than either of its componentsalone.

The preferred compound, methenamine phenylpropionate, when tested by theagar plate method will show a bactericidal action of 1:3000 against B.0012 and Staphylococcus aureus. The compounds described are non-toxicand are well tolerated by experimental animals and are valuaable astherapeutic agents.

We have described our invention in detail and with respect to preferredforms, as many Widely different embodiments of this invention may bemade without departing from the spirit and scope therein. We do notintend to limit ourselves to the specific embodiments herein set forth,except as indicated in the claims.

What we claim is:

1. As a new medicinal product, the compound obtained by reactingmethenamine with an aromatic acid of the formula: ARCOOH where A is anaromatic radical and R is a member of the class consisting of saturatedaliphatic hydrocarbon radicals, unsaturated aliphatic hydrocarbonradicals and hydroxy-substituted aliphatic hydrocarbon radicals.

2. As a new medicinal product, the compound obtained by reactingmethenamine with an arcmatic acid of the formula: ARCOOH where A is anaromatic radical and R. is a saturated aliphatic hydrocarbon radical.

3. As a new medicinal product, the compound obtained by reactingmethenamine with an arcmatic acid of the formula: ARCOOI-I Where A is anaromatic radical and R is an unsaturated aliphatic hydrocarbon radical.

4. As a new medicinal product, the compound obtained by reactingmethenamine with an arcmatic acid of the formula ARCOOH where A is anaromatic radical and R is a hydroxy-substituted aliphatic hydrocarbonradical.

5. As a new medicinal product, methenamine phenyl propionate, a Whitecrystalline compound obtained by reacting methenamine andphenylpropionic acid in a non-aqueous organic solvent.

6. As a new medicinal product, methenamine cinnamate, a whitecrystalline product obtained by reacting methenamine and cinnamic acidin a non-aqueous organic solvent.

'7. As a new medicinal product, methenamine phenyl hydroxy propionate,obtained by reacting methenamine with oxyphenyl propionic acid in anon-aqueous solvent.

8. As a new medicinal product an aromatic acid salt of methenamine ofthe following general formula:

Where n is less than 7.

9. As a new medicinal product, an aromatic acid salt of methenamine ofthe following general formula:

where n is less than 7.

10. As a new medicinal product an aromatic acid salt of methenamine ofthe following general formula:

where n is less than 7.

MONROE D. EDELMAN. EDMOND T. TISZA.

